title: Fatty acids differentially regulate insulin resistance through endoplasm reticulum stress-mediated induction of tribbles homologue 3: a potential link between dietary fat composition and the pathophysiological outcomes of obesity.
abstract: OBJECTIVE
  Previous studies have shown that saturated fatty acids cause insulin resistance (IR) that is prevented by unsaturated fatty acids. Tribbles homologue 3 (TRIB3) is a putative endogenous inhibitor of insulin signalling, but its role in insulin signalling is controversial. This study aimed to determine whether fatty acids regulate IR via TRIB3.
  
  
  METHODS
  We treated HepG2 cells with saturated and unsaturated fatty acids and evaluated TRIB3 expression. We then tested whether regulation of TRIB3 occurred through endoplasmic reticulum (ER) stress, and whether modulating TRIB3 and ER stress marker genes was necessary and/or sufficient for regulation of insulin signalling. To test the in vivo significance of this mechanism, we fed mice obesogenic diets with different fatty acid profiles and assessed physiological variables of diabetes, ER stress markers and Trib3 expression in the liver.
  
  
  RESULTS
  Our data show that fatty acids differentially regulate IR through ER stress-mediated induction of TRIB3. Intriguingly, a standard and widely used obesogenic diet high in unsaturated fats failed to induce ER stress, TRIB3 or IR. However, an alternative obesogenic diet with lower unsaturated fat recapitulated the cell studies by causing ER stress, TRIB3 induction and IR.
  
  
  CONCLUSIONS
  This study revealed a novel mechanism linking dietary fat composition to IR. Given the emerging roles for ER stress in non-alcoholic liver disease, we conclude that dietary fat composition rather than total amount may mediate hepatic pathology associated with obesity.
authors.affiliation: Department of Biochemistry and Molecular Biology, the Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: T
authors.initials: T
authors.lastname: Geng
authors.forename: W
authors.initials: W
authors.lastname: Hu
authors.forename: M H
authors.initials: MH
authors.lastname: Broadwater
authors.forename: J M
authors.initials: JM
authors.lastname: Snider
authors.forename: J
authors.initials: J
authors.lastname: Bielawski
authors.forename: S B
authors.initials: SB
authors.lastname: Russo
authors.forename: J H
authors.initials: JH
authors.lastname: Schwacke
authors.forename: J
authors.initials: J
authors.lastname: Ross
authors.forename: L A
authors.initials: LA
authors.lastname: Cowart
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004041:Dietary Fats; D005227:Fatty Acids; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D017346:Protein Serine-Threonine Kinases